Male sexual dysfunction, or impotence, may be manifested in various ways: loss of desire, inability to obtain or maintain an erection, premature ejaculation, absence of emission, inability to achieve orgasm. The organic causes of erectile impotence can be grouped into endocrine, drug, local, neurologic, and vascular causes. Vascular insufficiency causes impotence because blood flow into the vascular network of the penis is insufficient to obtain (or maintain) the erect state. Likewise, occlusion in smaller vessels supplying the penis can also lead to impotence. Together with neuropathy, vascular insufficiency contributes to the impotence in many men with diabetes mellitus.
Erectile impotence or dysfunction (ED) may be defined as an inability to achieve or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population as a whole, and the incidence increases with age up to 50 years. Between 18 and 75% of the male population between 55 and 80 years of age are impotent. In the U.S.A. alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than psychogenic origin.
Medical therapy with androgens offers little more than placebo benefit except in hypogonadal men. Surgical therapy may be useful in the treatment of decreased potency related to aortic obstruction; however, potency can be lost rather than improved after aortic operation if the autonomic nerve supply to the penis is damaged. A useful surgical technique for improvement of potency in refractory patients such as individuals with diabetic neuropathy is the implantation of a penile prosthesis, e.g., the insertion within the corpora of a small, blunt, SILASTIC® rod. The patient must be made aware that full erection is not produced and that the device only prevents buckling during intercourse. Furthermore, the complication rate is high in some patients. Alternatively, an inflatable prosthetic device has been devised for implantation on either side of the corpora. A connecting reservoir of material is placed in the perivesicular space and pumps are located in the scrotum. By means of these pumps the penis can be made to become nearly fully erect at the appropriate time and to relax after intercourse.
Prostaglandin E-1 (PGE-1; Alprostadil) has been employed successfully in the treatment of erectile dysfunction. Injections of 10 to 60 μg of PGE-1 directly into the corpora cavernosa of the penis have been found to be effective in producing erections sufficient to allow intercourse. The erections are reported to last 30 minutes to one hour, but the dangers associated with self-injection, e.g., infection, trauma, etc. make this treatment method highly undesirable. PGE-1 has also been administered by placing a pellet containing 125 to 1000 μg of the drug into the male urethra using a specially-designed device. This approach, while avoiding the dangers of self-injection, still involves the danger of producing a urethral infection. Other drawbacks include difficulty in adjusting the dose, trauma to the urethra, and vaginal burning in the female partner.
Medical treatment of erectile dysfunction has been attempted using intracavernosal (i.c.) injection of vasoactive substances, and good results have been claimed with phenoxybenzamine, phentolamine, papaverine, and prostaglandin E1, either alone or in combination; however, pain, priapism, and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
Sublingual administration of apomorphine has been reported to restore normal erectile function through its effect on brain chemistry. However, the response requires 20 to 40 minutes following administration, and apomorphine was found to be effective in returning sexual potency only to about 70% of men whose dysfunction had psychological origins.
The physiologic mechanism of erection of the penis involves the local release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme cyclic guanosine monophosphate (cGMP) producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil (VIAGRA®)) is reported to be a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolizing cyclic GMP formed in the corpus cavernosum. Since sildenafil is a potent inhibitor of PDE5 in the corpus cavernosum, it is believed to enhance the effect of nitric oxide, thereby increasing cavernosal blood flow in the penis, especially with sexual stimulation. Inhibitors of cyclic guanosine 3′, 5′-monophosphate phosphodiesterases (cGMP PDEs), such as sildenafil, are useful in the treatment of ED. As disclosed in PCT Publication WO 94/28902, sildenafil compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration. Inasmuch as sildenafil at the currently recommended doses of 25-100 mg has little effect in the absence of sexual stimulation, sildenafil is believed to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation. See, for example, Goldstein et al., The New England Journal of Medicine, 338, 1397-1404 (1998). The localized mechanism by which cGMP stimulates relaxation of the smooth muscles has not been elucidated.
In dose-response studies, increasing doses of sildenafil (25 to 100 mg) reportedly increased the erectogenic efficacy of sildenafil. However, the time to onset of action of periorally administered drugs is long and highly variable, due to differences in absorption based on a wide variety of factors, from the size and age of the patient to the interval since, and size and composition of, the last meal consumed by the patient. However, the oral administration of sildenafil is also accompanied by dose-responsive undesirable side effects. At dosages higher than 50 milligrams, the incidence of such side effects as abnormal vision problems ranging from blue or green halo effects to blurring, dyspepsia, nasal congestion, blinding headaches, flushing redness, diarrhea, dizziness, rash, and urinary tract infection increases. Other more serious side effects have been reported, such as syncope (loss of consciousness), priapism (erection lasting 4 hours or more) and increased cardiac risk (coital coronaries), can be brought on in some cases by physiological predisposition, adverse drug interaction or potentiation, or by drug abuse.
In addition, consistent with its known effects on the NO/cGMP pathway, sildenafil has been shown to potentiate the hypotensive effects of nitrates. Hypotension crisis can result from the combination of sildenafil citrate and organic nitrates, causing, in some cases death, so its administration to patients who are concurrently using organic nitrates (such as nitroglycerin) in any form is contraindicated. Moreover, the long-term effects of large doses of sildenafil containing drugs is not known. See, for example, Handy B., Time, 50-57 (May 4, 1998).
In a healthy vasculature, vascular smooth muscle (VSM) is covered by a monolayer of endothelial cells (FIG. 1). Healthy VSM contracts in response to vasoconstrictor agonists, including norepinephrine (NE). Lamb and Barna, Am. J. Physiol., 275, H151 (1998). Disruption of the endothelial layer has been shown to increase sensitivity to these agonists. These findings are consistent with studies which showed that changes in the basal production of NO alters VSM responsiveness to vasoconstrictors. Joulow-Schaeffer et al., Am. J. Physiol., 259, R38 (1990); Rees et al., Proc. Natl. Acad. Sci. USA, 86, 3375 (1989); Wiklund et al., Eur. J. Pharmacol., 185, 123 (1990). Medical procedures, such as balloon angioplasty, or disease-induced or genetically-influenced pathologies, such as diabetes and hypertension, create the risk or predisposition for compromised vascular tissue, i.e., damage to the endothelial cell monolayer. In addition, endothelial damage in itself may exacerbate these pathologic processes and contribute to symptoms which are associated with them. For instance, coronary artery disease results in localized endothelial damage, and sudden surges in natural vasoconstrictors (such as NE) can cause heart failure. Previous treatments for these endothelially compromised patients have been limited to chemicals agents which cause system-wide VSM relaxation, and consequently, frequently cause side effects such as orthostasis (dizziness) due to transient low blood pressure during certain activities.
Chloride ion channels are present in VSM (Klockner, Pflugers Arch., 424 231 (1991); Lamb et al., Circ. Res., 75 742 (1994)) and have been shown to be activated by vasoconstrictor agonists (Klockner and Isenberg, Pflugers Arch., 418, 168 (1991); Pacaud et al., Br. J. Pharmacol., 97 139 (1989)). Chloride ion currents have also been shown to contribute functionally to norepinephrine-induced contraction of normal vasculature. Lamb and Barna, Am. J. Physiol., 275 H151 (1998). In that study, tamoxifen was shown to have no effect on the norepinephrine-induced contraction of normal vasculature (vasculature with intact endothelium). In Lamb and Barna, Am. J. Physiol., 275, H161 (1998), the endothelium was shown to modulate the contribution of the chloride currents to norepinephrine-induced VSM constriction. The effects of tamoxifen on endothelium-compromised tissue was not studied, since no effect was seen in normal tissues. In other studies, a particular chloride ion channel, “CLC3”, was shown to be responsible for swelling-induced chloride conductance. Duan et al., Nature 390, 417 (1997). Tamoxifen was shown to block the ion channel responsible for swelling-induced chloride conductance, a result which had previously been demonstrated. Nilius et al., 428 Pflugers Arch 364 (1994).
The effects of tamoxifen on estrogen levels, and concomitant effects on other systems, including NE and dopamine expression, have also been studied. Kocsis et al., Br J Exp Path, 157 (1988); Etgen and Petitti, J Neurochem, 49, 1732 (1987); Baksi et al., Neuropharm, 20, 1163 (1981). Moreover, a method for treating peripheral vasoconstriction with tamoxifen citrate has been disclosed in U.S. Pat. No. 5,470,883. In that patent, the anti-estrogen effects of tamoxifen were said to be responsible for reducing the peripheral vasoconstriction of exogenously-administered adrenergic compound.
There exists a need for a method of treating a patient with compromised vascular tissue, e.g., an endothelially-compromised patient, a patient having erectile dysfunction.